Long-term changes in the cellular properties of neurons (i.e., sensitization) has been thought to be one mechanism mediating both continued drug abuse and relapse in individuals who have been abstinent from drug use. However, this leaves the question of what leads to the initiation and maintenance of drug use prior to the induction of sensitization following repeated use of drugs. Like drugs of abuse, sexual behavior will activate the mesoaccumbens dopamine pathway in female hamsters. Prior sexual experience will sensitize the dopamine response to sexual interactions and produce behavioral sensitization to the initial presentation of amphetamine (i.e., cross-sensitization) in otherwise drug-naive animals. The long-term goal of this project will be to compare at the anatomical and cellular levels the degree to which motivated behaviors and drugs of abuse have common mechanisms of sensitization of dopamine pathways. There are 4 specific aims of this project. The first two aims will analyze the properties of sensitization produced by sexual experience using microdialysis measurements of extracellular dopamine concentrations and postsynaptic activation using c-Fos immunocytochemistry. The persistence of sensitization of extracellular dopamine responses in the nucleus accumbens, responsivity to a novel environment, cross-sensitization to amphetamine treatment will be studied. The third aim is to examine presynaptic mechanisms mediating the sensitized dopamine response in microdialysis studies. Potential long-term effects of sexual experience on autoreceptor function and the dopamine transporter will be explored in this aim. The fourth aim will determine whether there are enduring postsynaptic changes following sexual experience. One experiment will test whether there is a decrease in dopamine D1 receptor internalization in sexually-experienced females. A second experiment will assess responsivity of cAMP accumulation to activation of D1 receptors as a function of prior sexual experience. A final aim will examine possible long-term changes in dopamine D1 and D2 receptors following sexual experience. Together, these experiments will pave the way for future studies comparing neural changes produced by behaviors relevant to the natural history of animals with those induced by repeated exposure to drugs of abuse.